Gonadoliberin (also referred to as gonadotropin releasing hormone, Gn-RH, luteinizing and folliculus stimulating hormone, releasing hormone, LH(FSH-RH) and its known derivatives are capable of releasing the luteinizing and folliculus stimulating hormones (LH and FSH).
It is known in the art [M. Monahan et al., Biochemistry 12, 4616-4620 (1973)] that those gonadoliberin derivatives in which glycine in the 6-position is replaced by certain D-amino acids have a surplus effect related to gonadoliberin. This increase in the activity is most expressed in case of the compounds which contain D-tryptophane or D-tert.butyl-serine in the 6-position (J. Sandow et al., Control of Ovulation, Butterworths, London, 1978, pp. 49-70).
According to Nestor et al.[J. Med. Chem. 25, 795-801 (1982), U.S. Pat. No. 4,234,571] by replacing the glycine in the 6-position of gonadoliberin by D-amino acids having a highly lipophilic side-chain also effective gonadoliberin analogues can be prepared.
It is further known that the biological activity of gonadoliberin can further be increased by replacing the glycine-amide group in the 10-position with amide groups containing aliphatic carbon chain [M. Fujino et al., J.Med.Chem. 16, 1144-1147 (1973)].
According to Coy, D. H., Labrie, F., Savary, M., Coy, E. J., Schally, A. V. Biochem. Biophys. Res. Commun. 67, 576-582 (1975), potent gonadoliberin derivatives can be obtained also by replacing the 6-glycine in gonadoliberin or in a corresponding amide by a D-phenylalanyl group.
The invention relates to new gonadoliberin derivatives which show a better biological activity than their known analogues.
According to another aspect of the invention we provide a process for the preparation of the new nona- and decapeptide derivatives of the formula (I) (X and Y are as defined above), by which in place of the 6-glycine group other amino acids can be incorporated with a good yield, without racemization.